CN105330569A - Preparation method of (R)-2-(N-tertbutyloxycarbonylamino)biphenylpropanol - Google Patents
Preparation method of (R)-2-(N-tertbutyloxycarbonylamino)biphenylpropanol Download PDFInfo
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- 0 CC(N[C@](Cc(cc1)ccc1-c1ccccc1)C(O*)=O)=O Chemical compound CC(N[C@](Cc(cc1)ccc1-c1ccccc1)C(O*)=O)=O 0.000 description 7
- TYQICOFAZDVKMK-UHFFFAOYSA-N CC(C)(C)OC(NC(Cc(cc1)ccc1-c1ccccc1)CO)=O Chemical compound CC(C)(C)OC(NC(Cc(cc1)ccc1-c1ccccc1)CO)=O TYQICOFAZDVKMK-UHFFFAOYSA-N 0.000 description 1
- JCZLABDVDPYLRZ-UHFFFAOYSA-N NC(Cc(cc1)ccc1-c1ccccc1)C(O)=O Chemical compound NC(Cc(cc1)ccc1-c1ccccc1)C(O)=O JCZLABDVDPYLRZ-UHFFFAOYSA-N 0.000 description 1
- JCZLABDVDPYLRZ-CQSZACIVSA-N N[C@H](Cc(cc1)ccc1-c1ccccc1)C(O)=O Chemical compound N[C@H](Cc(cc1)ccc1-c1ccccc1)C(O)=O JCZLABDVDPYLRZ-CQSZACIVSA-N 0.000 description 1
- QIYDZMXXQWNWHJ-UVTDQMKNSA-N O=C(/C(/N1)=C/c(cc2)ccc2-c2ccccc2)NC1=O Chemical compound O=C(/C(/N1)=C/c(cc2)ccc2-c2ccccc2)NC1=O QIYDZMXXQWNWHJ-UVTDQMKNSA-N 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N O=C(CN1)NC1=O Chemical compound O=C(CN1)NC1=O WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- ISDBWOPVZKNQDW-UHFFFAOYSA-N O=Cc(cc1)ccc1-c1ccccc1 Chemical compound O=Cc(cc1)ccc1-c1ccccc1 ISDBWOPVZKNQDW-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a preparation method of (R)-2-(N-tertbutyloxycarbonylamino)biphenylpropanol represented by formula (I). The method comprises the following steps: carrying out an Erlenmeyer-Plochl cyclization reaction on biphenylcarboxaldehyde and N-acylglycine, hydrolyzing or alcoholyzing, and carrying out asymmetric hydrogenation to obtain (R)-N-acylbiphenylalanine or an ester thereof; and carrying out acid hydrolysis, reduction and amino protection on the (R)-N-acylbiphenylalanine or the ester thereof, or carrying out reduction, acid hydrolysis and amino protection on the (R)-N-acylbiphenylalanine or the ester thereof, or directly reducing the (R)-N-acylbiphenylalanine or the ester thereof in order to obtain the product (R)-2-(N-tertbutyloxycarbonylamino)biphenylpropanol. The product is a key intermediate of Sacubitril (AHU-377) which is one of a novel blood pressure reducing medicine LCZ696. The method has the advantages of easily available raw materials, and suitableness for industrial production.
Description
Technical field
The present invention relates to the preparation method of a kind of husky storehouse than bent (Sacubitril, AHU-337) intermediate, be specifically related to the preparation method of one (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol.
Background technology
LCZ696 is a kind of Novel blood pressure-reducing medicine developed by Novartis (Novartis) company, or the ARNI inhibitor class medicine of first success of the test.ARNI inhibitor is a kind of hypertensin inhibitor, but it can strengthen the effect of endogenous natriuretic peptide (vasodilator) simultaneously.LCZ696 combines the Valsartan (Diovan of Novartis, popular name: valsartan) and experimental drug Sacubitril (AHU-377) two kinds of components, Diovan can improve vasorelaxation, stimulate body excretes sodium and water, Sacubitril then has the mechanism of action blocking and threaten and be responsible for 2 peptide species reduced blood pressure, both play pharmacological action by reaction forming together jointly, thus this medical instrument has the double inhibition effect of angiotensin-ii receptor and enkephalinase, clinical manifestation goes out unique binding mode, be believed to the strain reducing failure heart, be better than the hypotensive effect of standard drug, and the rapid passage obtaining U.S. FDA and European Union EMEA evaluates qualification.Industry generally believes that LCZ696 will bring the innovation of traditional heart failure treatment plan.
The chemistry of Sacubitril (AHU-377) is called: 4-[((2S, 4R)-1-((1,1'-biphenyl)-4-base)-5-oxyethyl group-4-methyl-5-oxo-pentane-2-base) amino]-4-ketobutyric acid (X), its structural formula is as follows:
The preparation method of Sacubitril (AHU-377) has more research report; its Patent US5217996, WO2008031567, WO2010136474 and WO2012025501 etc. report one with (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol for raw material; be oxidized to the ethyl esterified and amidate action synthesis target product of aldehyde, Witting reaction, basic hydrolysis, asymmetric hydrogenation, deprotection through alcohol, particular content is shown below:
According to above-mentioned report; raw material (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol is the key intermediate of preparation Sacubitril (AHU-377); it is a kind of chirality benzidino-alcohol compound; by carrying out carboxyl to (R)-biphenylalanine and ester thereof or carboxylicesters reduction reaction prepares corresponding alcohol, then target product can be obtained by amido protecting.
(R) preparation method of-biphenylalanine and ester thereof mainly contains following three kinds:
(1) take D-Tyrosine as raw material; D-(N-tertbutyloxycarbonyl) biphenyl propylhomoserin methyl esters (J.Med.Chem.1995 is generated by amido protecting, carboxyl ester, the activation of hydroxyl trifluoromethanesulfonic acid, Suzuki reaction; 38; 1689-1700.), particular content is shown below:
The method adopts expensive non-natural D-Tyrosine as starting material, and cost is high, and meanwhile, not only price is high for the material trifluoromethanesulfanhydride anhydride of use, and active extremely strong, and be the inflammable compound of severe corrosive, production operation requires high; The phenylo boric acid used is poisonous and harmful reagent, big for environment pollution.
(2) with biphenylcarboxaldehyde and N-acylglycine for raw material; by Erlenmeyer-Plochl cyclization; hydrolysis and hydrogenation obtain achiral N-acyl diphenylalanine (WO2011035569; CN200810200404); carry out fractionation by Chiral Amine again and obtain chirality N-acyl group biphenyl propylhomoserin (WO2010081410), particular content is as follows:
Although the method supplementary material is simple and easy to get, with low cost, use traditional method for splitting to carry out the acid of synthesis of chiral benzidino-, yield is low, and route is long, and cost is high, and competitive power is weak.
(3) with biphenylcarboxaldehyde and glycolylurea for starting raw material, split through Schiff reaction, shortening, biological enzyme, obtain chirality biphenylalanine (CN200780002319.6), particular content is as follows:
Although this technique obtains the optical purity of product more than 99.5%, biological enzyme disassemble technique requires high to reaction conditions, need strictly to control pH value in reaction, and concentration of substrate is low, produces difficulty greatly.And bioactive enzyme Alkalase is expensive, cost is high.
In addition; report in patent WO2014032627 with bromobiphenyl is raw material; first through grignard reaction; obtain target product (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol with the propylene oxide reaction of chirality, then ammonification, amido protecting again, particular content is shown below:
The method route is short, supplementary material relative low price, but in amination steps, use a large amount of poisonous and harmful reagent triphenylphosphines, and environmental pollution is large.Meanwhile, Grignard reagent is active strong, and operation requires high, produces difficulty greatly.
Find out thus, existing preparation scheme can not solve the synthesis of target compound well.Due to, be subject to all many-sided restrictions such as starting material, cost, equipment and environmental protection, not easily industrialization.Analyze the relative merits of existing operational path, use modern asymmetric catalytic technology, design and development goes out simple and easy, economic environmental protection and is convenient to industrialized new synthesis route, and the economic technology development for this target compound is significant.
Summary of the invention
The object of the invention is to for defect of the prior art, analyze commercial viability and the economic benefit of pertinent literature report, following operational path is selected to carry out study on the industrialization, its route comprises the following steps: adopt biphenylcarboxaldehyde and N-acylglycine to be starting material, obtains (R)-N-acyl diphenylalanine or ester through Erlenmeyer-Plochl ring-closure reaction, hydrolysis or alcoholysis, asymmetric hydrogenation; (R)-N-acyl diphenylalanine or ester are through acid hydrolysis, reduction, amido protecting or first reduction, acid hydrolysis again, amido protecting or direct-reduction obtain target product (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol.This operational path has the advantages that raw material is easy to get, concise in technology, production safety are reliable and stable, yield is high, optical purity is high, cost is low, is applicable to suitability for industrialized production.
The present invention specifically adopts following technical scheme:
A kind of preparation method such as formula (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in (I), described preparation method carries out as follows:
(1) Erlenmeyer-Plochl cyclization: under nitrogen protection,, under the existence of aceticanhydride and alkali, there is the oxazolone compound shown in Erlenmeyer-Plochl ring-closure reaction synthesis type (IV) in the N-acylglycine shown in the biphenylcarboxaldehyde shown in formula (II) and formula (III);
Described alkali is preferably sodium-acetate or Potassium ethanoate; Described temperature of reaction is preferably 85 ~ 100 DEG C; Described biphenylcarboxaldehyde is preferably 1:0.7 ~ 1.5:1 ~ 5:0.8 ~ 1.5 with the ratio of the amount of substance that feeds intake of N-acylglycine, aceticanhydride, alkali;
Wherein, R
1for methyl, phenyl or tert.-butoxy;
(2) hydrolysis or alcoholysis: the oxazolone compound shown in formula (IV) of step (1) gained, obtains the N-acyl group biphenyl propylene propylhomoserin shown in formula (V) or ester via hydrolysis or alcoholysis;
Described hydrolysing agent is preferably 0.1wt% ~ 10wt% aqueous sodium hydroxide solution or 0.1wt% ~ 10wt% potassium hydroxide aqueous solution; Described alcoholysis reagent is preferably 0.1wt% ~ 10wt% methanol solution of sodium methylate or 0.1wt% ~ 10wt% alcohol sodium alcohol solution; Described temperature of reaction is preferably 40 ~ 100 DEG C; The volumetric usage of described hydrolysing agent or alcoholysis reagent is preferably 3 ~ 5mL/g in the quality of oxazolone compound substrate formula (IV) Suo Shi;
Wherein, R
1for methyl, phenyl, tert.-butoxy; R
2for hydrogen, methyl or ethyl;
(3) asymmetric hydrogenation: the N-acyl group biphenyl propylene propylhomoserin shown in formula (V) of step (2) gained or ester are under rhodium metal-biphosphine ligand catalyst, there is asymmetric hydrogenation in organic solvent, obtain (the R)-N-acyl diphenylalanine shown in formula (VI) or ester;
Preferably, described temperature of reaction is 30 ~ 100 DEG C, in reaction system, hydrogen pressure is 0.5 ~ 3.0MPa, described reaction solvent is methyl alcohol, ethanol, Virahol, methylene dichloride or tetrahydrofuran (THF), the volumetric usage of described reaction solvent counts 4 ~ 6mL/g with the quality of substrate formula (V), described rhodium metal-biphosphine ligand catalyzer is (R)-[RhcodTCFP] BF4, [Rhcod (R)-DuanPhos] BF4, [Rhcod (R)-TangPhos] BF4, [Rhcod (R)-DuPhos] BF4, [Rhcod (R)-PhanePhos] BF4, [(R)-BinapRuClbenzene] Cl, [(R)-PPhosRuCl (p-cymene)] Cl, [(R)-xyl-PPhosRuCl (p-cymene)] Cl, shown in described rhodium metal-biphosphine ligand catalyzer and substrate formula (V), the ratio of the amount of substance that feeds intake of N-acyl group biphenyl propylene propylhomoserin or ester cpds is 1:10,000 ~ 120,000,
Wherein, R
1for methyl, phenyl or tert.-butoxy; R
2for hydrogen, methyl or ethyl;
(R)-N-acyl diphenylalanine shown in step (3) gained formula (VI) or ester; through hydrolysis, reduction, amido protecting, obtain (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in described formula (I).
Further, synthetic method of the present invention is carried out as follows:
Step (1) ~ (3) are same as described above;
(4-a) be hydrolyzed: (R)-N-acyl diphenylalanine shown in formula (VI) of step (3) gained or ester back hydrolysis under strong acid aqueous solution exists, synthesis (R)-biphenylalanine (formula VII);
Described strong acid aqueous solution is the aqueous hydrochloric acid of 5wt% ~ 30wt% or the aqueous sulfuric acid of 10wt% ~ 40wt%; The volumetric usage of described strong acid aqueous solution counts 4 ~ 6mL/g with the quality of substrate formula (VI);
(5-a) reduce: (the R)-biphenylalanine shown in formula (VII) of step (4-a) gained carries out (the 2R)-phenylaniline propyl alcohol shown in carboxyl reduction Reactive Synthesis formula (VIII) under sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system effect;
Described metal-salt system is alkaline earth metal chloride, lanthanide series metal muriate or transition metal chloride; The organic solvent that described carbonyl reduction reacts used is tetrahydrofuran (THF) or methyl alcohol; Described carbonyl reduction reaction is carried out under reflux conditions; In described sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system, sodium borohydride or POTASSIUM BOROHYDRIDE and metal-salt feeds intake amount of substance than being 1:0.1 ~ 1, preferred 1:0.5; Described carbonyl reduction reaction substrate formula (VII) is 1:1 ~ 5 with the amount of substance ratio that feeds intake of sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system; The volumetric usage of described organic solvent counts 8 ~ 12mL/g with the quality of substrate formula (VII);
(6) amido protecting: (the 2R)-phenylaniline propyl alcohol shown in formula (VIII) of step (5-a) gained in the basic conditions, react with tert-Butyl dicarbonate in organic solvent, (R)-3-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in synthesis final product formula (I);
Described alkaline condition alkali used is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, triethylamine or DMAP; Described organic solvent is water, methylene dichloride or tetrahydrofuran (THF); The temperature of reaction of described step (6) is 0 ~ 30 DEG C; (2R)-phenylaniline propyl alcohol shown in described formula (VIII) is 1:1 ~ 5:1 ~ 2 as reaction substrate and the ratio of the amount of substance that feeds intake of alkali, tert-Butyl dicarbonate; The volumetric usage of described organic solvent counts 5 ~ 10mL/g with the quality of substrate formula (VIII);
Or,
When step (3) gained formula (VI) shown in (R)-N-acyl diphenylalanine or ester for (the R)-N-Benzoylbiphenyl L-Ala shown in (the R)-N-acetyl biphenyl L-Ala shown in formula (VIa) or ester or formula (VIb) or ester time, synthetic method of the present invention is carried out as follows:
Wherein, R
2for hydrogen, methyl or ethyl;
Step (1) ~ (3) are same as described above;
(4-b) reduce: (the R)-N-acetyl biphenyl L-Ala shown in formula (VIa) of step (3) gained or ester or (the R)-N-Benzoylbiphenyl L-Ala shown in formula (VIb) or ester are under sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system effect, and (2R) shown in carboxyl reduction Reactive Synthesis formula (IXa)-(N-ethanoyl) phenylaniline propyl alcohol or (2R) shown in formula (IXb)-(N-benzoyl) phenylaniline propyl alcohol are carried out in backflow in organic solvent;
Described metal-salt system is alkaline earth metal chloride, lanthanide series metal muriate or transition metal chloride; The organic solvent that described carbonyl reduction reacts used is tetrahydrofuran (THF) or methyl alcohol; In described sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system, sodium borohydride or POTASSIUM BOROHYDRIDE and metal-salt feeds intake amount of substance than being 1:0.1 ~ 1, preferred 1:0.5; Described reduction reaction substrate formula (VIa) or formula (VIb) are 1:1 ~ 5 with the amount of substance ratio that feeds intake of sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system; The volumetric usage of described organic solvent counts 8 ~ 12mL/g with the quality of substrate formula (VII);
(5-b) be hydrolyzed: (2R) shown in formula (IXa)-(N-ethanoyl) the phenylaniline propyl alcohol of step (4-b) gained or (2R) shown in formula (IXb)-(N-benzoyl) phenylaniline propyl alcohol back hydrolysis under strong acid aqueous solution exists, (the 2R)-phenylaniline propyl alcohol shown in synthesis type (VIII);
Described strong acid aqueous solution is the aqueous hydrochloric acid of 5wt% ~ 30wt%, the aqueous sulfuric acid of 10wt% ~ 40wt%; The volumetric usage of described strong acid aqueous solution counts 4 ~ 6mL/g with the quality of substrate formula (VI);
(6) amido protecting: (the 2R)-phenylaniline propyl alcohol shown in formula (VIII) of step (5-a) gained in the basic conditions, react with tert-Butyl dicarbonate in organic solvent, (R)-3-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in synthesis final product formula (I);
Described alkaline condition alkali used is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, triethylamine or DMAP; Described organic solvent is water, methylene dichloride or tetrahydrofuran (THF); The temperature of reaction of described step (6) is 0 ~ 30 DEG C; (2R)-phenylaniline propyl alcohol shown in described formula (VIII) is 1:1 ~ 5:1 ~ 2 as reaction substrate and the ratio of the amount of substance that feeds intake of alkali, tert-Butyl dicarbonate; The volumetric usage of described organic solvent counts 5 ~ 10mL/g with the quality of substrate formula (VIII);
Or,
When (the R)-N-acyl diphenylalanine shown in formula (VI) or ester are for (the R)-N-tertbutyloxycarbonyl biphenylalanine shown in formula (VIc) or ester, synthetic method of the present invention is carried out as follows:
Wherein, R
2for hydrogen, methyl, ethyl;
Step (1) ~ (3) are same as described above;
(4-c) reduce: (the R)-N-tertbutyloxycarbonyl biphenylalanine shown in formula (VIc) of step (3) gained or ester are under sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system effect, and (R)-3-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in carboxyl reduction Reactive Synthesis synthesis final product formula (I) is carried out in backflow in organic solvent;
Described metal-salt system is alkaline earth metal chloride, lanthanide series metal muriate or transition metal chloride; Described reduction reaction organic solvent used is tetrahydrofuran (THF) or methyl alcohol; In described sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system, sodium borohydride or POTASSIUM BOROHYDRIDE and metal-salt feeds intake amount of substance than being 1:0.1-1, preferred 1:0.5; Described reduction reaction substrate formula (VIc) is 1:1 ~ 5 with the amount of substance ratio that feeds intake of sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system; The volumetric usage of described organic solvent counts 8 ~ 12mL/g with the quality of substrate formula (VII);
Synthetic method of the present invention, in step (1), preferably described biphenylcarboxaldehyde is 1:0.9 ~ 1.2:2 ~ 4:1 ~ 1.2 with the ratio of the amount of substance that feeds intake of N-acylglycine, aceticanhydride, alkali.
In step (2), preferably, described hydrolysing agent is 0.5wt% ~ 5wt% aqueous sodium hydroxide solution or 0.5wt% ~ 5wt% potassium hydroxide aqueous solution; Described alcoholysis reagent is 0.5wt% ~ 5wt% methanol solution of sodium methylate or 0.5wt% ~ 5wt% alcohol sodium alcohol solution.
In step (3), preferably, described rhodium metal-biphosphine ligand catalyzer is [Rhcod (R)-DuanPhos] BF4, [Rhcod (R)-TangPhos] BF4; Shown in preferably described rhodium metal-biphosphine ligand catalyzer and substrate formula (V), the ratio of the amount of substance that feeds intake of N-acyl group biphenyl propylene propylhomoserin or ester cpds is 1:50,000 ~ 100,000.
In step (4-a) or (5-b), preferably, described strong acid aqueous solution is the aqueous hydrochloric acid of 15wt% ~ 25wt%, the aqueous sulfuric acid of 25wt% ~ 35wt%.
In step (5-a) or (4-b) or (4-c), preferably, described metal-salt is aluminum chloride, chlorinated ketone, calcium chloride, lithium chloride, Manganous chloride tetrahydrate, Lanthanum trichloride, zinc chloride; Preferably described reaction substrate formula (VII) or formula (VIa) or formula (VIb) or formula (VIc) and sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system feed intake amount of substance than being 1:1.5 ~ 3.
In step (6), preferably described (the 2R)-phenylaniline propyl alcohol shown in reaction substrate formula (VIII) is 1:2 ~ 4:1.2 ~ 1.4 with the ratio of the amount of substance that feeds intake of alkali, tert-Butyl dicarbonate;
Relative to prior art, the beneficial effect of synthetic method of the present invention is:
First, the present invention's supplementary material used is all cheap and easy to get, and reaction conditions is gentle, and transformation efficiency is high, and cost is low, and economic benefit is large, and meanwhile, this technique is low for equipment requirements, simple to operate.
Secondly, the present invention adopts asymmetric catalytic technology to obtain chiral centre, and by the optimization of chiral screening of catalyst and reaction conditions, greatly reduce the usage quantity (be 1:50 with the ratio of the amount of substrate materials, 000 ~ 100,000) of catalyzer, simultaneously, obtain the ee value of more than 99.0%, reduce process costs, competitive power is strong.
Again, operational path of the present invention is short, selecting, under suitable supplementary material condition, can synthesize target product by three-step reaction, greatly reducing the unstable in industrialization is produced, improving comprehensive yield.
The present invention compared with prior art, maximum benefit be this operational path comprehensive consideration supplementary material, cost, the factors such as equipment and environmental protection, be a route that can realize industrialization, the economic technology development for this target compound is significant.
Embodiment
Below by way of specific embodiment, technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
Reaction formula 1:
Embodiment 1:(R)-N-acetyl biphenyl alanine ethyl ester
Step (1): (4Z)-4-biphenyl methylene-2-methyl isophthalic acid, 3-oxazole-5-ketone
Under nitrogen protection; acetylaminoacetic acid (0.45mol is dropped into successively in 1L there-necked flask; 52.7g), sodium acetate, anhydrous (0.5mol, 41.0g), acetic anhydride (1mol, 102.1g); mechanical stirring 30min under room temperature; slowly add biphenylcarboxaldehyde (0.5mol, 91.1g), be heated to 90 DEG C; keep temperature of reaction system at 85 ~ 95 DEG C, TLC tracks to raw material point and reacts completely.Close heating, ice bath is cooled to 0 ~ 5 DEG C, has a large amount of yellow solid to separate out, and leaves standstill crystallization 6 hours.Take out material, vacuum-drying, obtain yellow solid product (4Z)-4-biphenyl methylene-2-methyl isophthalic acid, 3-oxazole-5-ketone 102.5g, yield 86.5%.
Step (2): (Z)-2-acetylaminohydroxyphenylarsonic acid 3-biphenyl ethyl propenoate
Under room temperature, in 1L there-necked flask, add the product (0.35mol, 92.2g) of step 1 gained and the alcohol sodium alcohol solution 460mL of 2%, mechanical stirring, be heated to 80 DEG C, back flow reaction, TLC tracks to raw material point and reacts completely, ice bath is cooled to 0 ~ 5 DEG C, leave standstill crystallization 3 hours, suction filtration, vacuum-drying, obtain white solid product (Z)-2-acetylaminohydroxyphenylarsonic acid 3-biphenyl ethyl propenoate 101.3g, yield 93.6%.
Step (3): (R)-N-acetyl biphenyl alanine ethyl ester
In the autoclave of 2L, add product (0.3mol, 92.8g) and the ethanol 550mL of step 2 gained, stir, logical nitrogen replacement oxygen 3 times.After having replaced, continue logical nitrogen protection.Then, drop into chiral catalyst [Rhcod (R)-DuanPhos] BF4 (3 μm of ol, 2.1mg) at dog-house, cover tightly dog-house rapidly.Logical hydrogen exchange nitrogen 3 times.After completing, continue logical hydrogen to 3.0Mpa, Heating temperature is set at 80 DEG C, control the temperature of reaction system at 75 ~ 85 DEG C.TLC tracks to raw material point to reacting completely.Venting hydrogen, with nitrogen replacement 3 times, then, be pressed out in 1L single port flask by material with nitrogen, concentrating under reduced pressure obtains crude white solid.Add the methyl tertiary butyl ether making beating of product 5 times amount; suction filtration; filter cake 50mL methyl tertiary butyl ether washs; vacuum-drying; obtain white solid purified product (R)-N-acetyl biphenyl alanine ethyl ester 86.2g; yield 92.3%, chemical purity 99.5%, optical purity 99.3% (HPLC).
1H-NMR(CDCl
3,400MHz)δ7.52-7.57(m,4H,Ar-H),7.35-7.42(m,5H,Ar-H),6.04(d,1H,J＝6.0Hz,NH),5.03(dd,1H,J
1＝6.8Hz,J
2＝7.2Hz,CH),3.92(q,2H,J＝7.6Hz,CH
2),3.52(dd,1H,J
1＝7.2Hz,J
2＝13.6Hz,CH
2),3.41(dd,1H,J
1＝6.8Hz,J
2＝13.6Hz,CH
2),2.05(s,3H,CH
3),1.32(t,J＝7.6Hz,CH
3).
Embodiment 2:(R)-N-Benzoylbiphenyl alanine methyl ester
Step (1): (4Z)-4-biphenyl methylene-2-phenyl-1,3-oxazoles-5-ketone
Under nitrogen protection; HIPPURIC ACID (0.5mol is dropped into successively in 1L there-necked flask; 89.6g), Glacial acetic acid potassium (0.6mol, 58.9g), acetic anhydride (2mol, 204.2g); mechanical stirring 30min under room temperature; slowly add biphenylcarboxaldehyde (0.5mol, 91.1g), be heated to 95 DEG C; keep temperature of reaction system at 90 ~ 100 DEG C, TLC tracks to raw material point and reacts completely.Close heating, ice bath is cooled to 0 ~ 5 DEG C, has a large amount of yellow solid to separate out, and leaves standstill crystallization 6 hours.Take out material, vacuum-drying, obtain yellow solid product (4Z)-4-biphenyl methylene-2-phenyl-1,3-oxazoles-5-ketone 150.3g, yield 92.4%.
Step (2): (Z)-2-benzamido-3-biphenyl methyl acrylate
Under room temperature, in 1L there-necked flask, add the product (0.45mol, 146.6g) of step 1 gained and the methanol solution of sodium methylate 580mL of 0.5%, mechanical stirring, be heated to 65 DEG C, back flow reaction, TLC tracks to raw material point and reacts completely, ice bath is cooled to 0 ~ 5 DEG C, leave standstill crystallization 3 hours, suction filtration, vacuum-drying, obtain white solid product (Z)-2-benzamido-3-biphenyl methyl acrylate 153.4g, yield 95.4%.
Step (3): (R)-N-Benzoylbiphenyl alanine methyl ester
In the autoclave of 2L, add product (0.4mol, 143.0g) and the methyl alcohol 570mL of step 2 gained, stir, logical nitrogen replacement oxygen 3 times.After having replaced, continue logical nitrogen protection.Then, drop into chiral catalyst [Rhcod (R)-TangPhos] BF4 (5 μm of ol, 2.9mg) at dog-house, cover tightly dog-house rapidly.Logical hydrogen exchange nitrogen 3 times.After completing, continue logical hydrogen to 0.5Mpa, Heating temperature is set at 65 DEG C, control the temperature of reaction system at 60 ~ 70 DEG C.TLC tracks to raw material point to reacting completely.Venting hydrogen, with nitrogen replacement 3 times, then, be pressed out in 1L single port flask by material with nitrogen, concentrating under reduced pressure obtains crude white solid.Add the methyl tertiary butyl ether making beating of product 5 times amount; suction filtration; filter cake 50mL methyl tertiary butyl ether washs; vacuum-drying; obtain white solid purified product (R)-N-Benzoylbiphenyl alanine methyl ester 133.8g; yield 93.1%, chemical purity 99.4%, optical purity 99.5% (HPLC).
1H-NMR(CDCl
3,400MHz)δ7.90(d,2H,J＝6.4Hz,Ar-H),7.51-7.57(m,7H,Ar-H),7.38-7.45(m,5H,Ar-H),6.74(dd,1H,J＝5.6Hz,NH),5.09(dd,1H,J
1＝7.2Hz,J
2＝7.6Hz,CH),3.77(s,3H,CH
3),3.45(dd,1H,J
1＝7.2Hz,J
2＝14.0Hz,CH
2),3.31(dd,1H,J
1＝7.6Hz,J
2＝14.0Hz,CH
2).
Embodiment 3:(R)-N-tertbutyloxycarbonyl biphenylalanine
Step (1): (4Z)-4-biphenyl methylene-2-tert.-butoxy-1,3-oxazoles-5-ketone
Under nitrogen protection; N-t-butoxycarbonyl glycine (0.6mol is dropped into successively in 1L there-necked flask; 105.1g), sodium acetate, anhydrous (0.55mol, 45.1g), acetic anhydride (1.5mol, 153.1g); mechanical stirring 30min under room temperature; slowly add biphenylcarboxaldehyde (0.5mol, 91.1g), be heated to 90 DEG C; keep temperature of reaction system at 85 ~ 95 DEG C, TLC tracks to raw material point and reacts completely.Close heating, ice bath is cooled to 0 ~ 5 DEG C, has a large amount of yellow solid to separate out, and leaves standstill crystallization 6 hours.Take out material, vacuum-drying, obtain yellow solid product (4Z)-4-biphenyl methylene-2-tert.-butoxy-1,3-oxazoles-5-ketone 126.4g, yield 78.7%.
Step (2): (Z)-2-t-butoxycarbonyl amino-3-biphenyl vinylformic acid
Under room temperature, in 1L there-necked flask, add the product (0.35mol, 112.5g) of step 1 gained and the sodium hydroxide solution 350mL of 5%, mechanical stirring, be heated to 100 DEG C, back flow reaction, TLC tracks to raw material point and reacts completely, ice bath is cooled to 0 ~ 5 DEG C, leave standstill crystallization 3 hours, suction filtration, vacuum-drying, obtain white solid product (Z)-2-t-butoxycarbonyl amino-3-biphenyl vinylformic acid 107.0g, yield 90.1%.
Step (3): (R)-N-tertbutyloxycarbonyl biphenylalanine
In the autoclave of 2L, add product (0.3mol, 101.8g) and the Virahol 510mL of step 2 gained, stir, logical nitrogen replacement oxygen 3 times.After having replaced, continue logical nitrogen protection.Then, drop into chiral catalyst [Rhcod (R)-DuanPhos] BF4 (6 μm of ol, 4.1mg) at dog-house, cover tightly dog-house rapidly.Logical hydrogen exchange nitrogen 3 times.After completing, continue logical hydrogen to 2.0Mpa, Heating temperature is set at 85 DEG C, control the temperature of reaction system at 80 ~ 90 DEG C.TLC tracks to raw material point to reacting completely.Venting hydrogen, with nitrogen replacement 3 times, then, be pressed out in 1L single port flask by material with nitrogen, concentrating under reduced pressure obtains crude white solid.Add the methyl tertiary butyl ether making beating of product 5 times amount, suction filtration, filter cake 50mL methyl tertiary butyl ether washs, vacuum-drying, obtain white solid purified product (R)-N-tertbutyloxycarbonyl biphenylalanine 92.4g, yield 90.2%, chemical purity 99.1%, optical purity 99.2% (HPLC).
1H-NMR(CDCl
3,400MHz)δ12.6(s,1H,OH),7.51-7.59(m,4H,Ar-H),7.43(d,2H,J＝8.0Hz,Ar-H),7.38(dd,1H,J
1＝7.6Hz,J
2＝8.0Hz,Ar-H),7.33(d,2H,J＝7.6Hz,Ar-H),6.17(d,1H,J＝5.6Hz,NH),5.01(dd,1H,J
1＝6.8Hz,J
2＝7.2Hz,CH),3.47(dd,1H,J
1＝6.8Hz,J
2＝13.6Hz,CH
2)；3.35(dd,1H,J
1＝6.8Hz,J
2＝13.6Hz,CH
2),1.47(s,9H).
Reaction formula 2:
Embodiment 4:(R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol
Step (4-a): (R)-biphenylalanine
In the there-necked flask of 500mL, add 15% aqueous hydrochloric acid 180mL of (R)-N-acetyl biphenyl alanine ethyl ester (0.1mol, 31.1g) and new preparation, reflux.TLC tracks to raw material point and reacts completely, and close heating, ice bath is cooled to 0 ~ 5 DEG C, slowly adds sodium hydroxide solution adjust ph to 5 ~ 6 of 10%, has a large amount of white solid to separate out.Suction filtration, vacuum-drying, obtains white solid product (R)-biphenylalanine 22.3g, and yield is 91.7%, chemical purity 99.3%, optical purity 99.0% (HPLC).
1H-NMR(DMSO,400MHz)δ12.53(s,1H,OH),7.47-7.53(m,4H,Ar-H),7.31-7.43(m,5H,Ar-H)；5.13(d,2H,J＝3.2Hz,NH
2),4.63(dd,1H,J
1＝6.8Hz,J
2＝7.2Hz,CH),3.17-3.25(m,2H,CH
2).
Step (5-a): (R)-phenylaniline propanol hydrochloride
Tetrahydrofuran (THF) 180mL, AlCl is added in the there-necked flask of 1L
3(0.0675mol, 9g) and NaBH
4(0.135mol, 5.1g), stirring at room temperature 1h, then the 1h that refluxes, stratification, get supernatant liquid, add the product (0.09mol, 21.7g) of step (4-a) gained, reflux, TLC tracks to raw material point and reacts completely, ice bath is cooled to 0 ~ 5 DEG C, adds the dilution of 200mL methyl tertiary butyl ether, adds suitable quantity of water termination reaction, add 20% aqueous sodium hydroxide solution 150mL again and stir 30min, filter, filter cake (3 × 20mL) methyl tertiary butyl ether washing, merges organic layer, anhydrous sodium sulfate drying, removes solvent under reduced pressure and obtains colorless oil.The ethanolic soln adding oily matter 5 times amount is clearly molten, and ice bath is cooled to 0 ~ 5 DEG C, drips concentrated hydrochloric acid, has a large amount of white solid to separate out.Suction filtration, vacuum-drying, obtain white solid product (R)-phenylaniline propanol hydrochloride 17.7g, yield is 74.6%, chemical purity 98.3%, optical purity 99.1% (HPLC).
1H-NMR(DMSO,400MHz)δ8.62(s,3H,NH
3 +),7.50-7.57(m,4H,Ar-H),7.28-7.37(m,5H,Ar-H),4.78(s,1H,OH),3.65-3.69(m,1H,CH),3.34(dd,J
1＝6.0Hz,J
2＝13.6Hz,CH
2),3.28(dd,1H,J
1＝5.6Hz,J
2＝14.0Hz,CH
2),2.83(dd,1H,J
1＝5.6Hz,J
2＝14.0Hz,CH
2),2.57(dd,1H,J
1＝6.0Hz,J
2＝14.0Hz,CH
2).
Step (6): (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol
In 500mL there-necked flask, add the product (0.05mol, 13.1g) of step (5-a) gained, sodium carbonate (0.1mol, 10.6g) and water 130mL, mechanical stirring, ice bath is cooled to 0 ~ 5 DEG C, adds tert-Butyl dicarbonate (0.06mol, 13.1g), remove ice bath, room temperature 25 ~ 30 DEG C reaction, has solid to separate out, and TLC tracks to raw material point and reacts completely.Suction filtration, vacuum-drying, obtains white solid product (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol 13.8g, yield is 84.3%, chemical purity 99.2%, optical purity 99.0% (HPLC), specific rotation+18.6 ° of (c=1, H
2o, 20 DEG C).
1H-NMR(DMSO,400MHz)δ7.53-7.61(m,4H,Ar-H),7.43(d,2H,J＝7.6Hz,Ar-H),7.32(dd,1H,J
1＝7.6Hz,J
2＝8.0Hz,Ar-H),7.28(d,2H,J＝7.6Hz,Ar-H),6.62(d,1H,J＝7.2Hz,NH),4.72(s,1H,OH),3.61-3.65(m,1H,CH),3.37(dd,1H,J
1＝6.4Hz,J
2＝13.6Hz,CH
2),3.31(dd,1H,J
1＝6.8Hz,J
2＝13.6Hz,CH
2),2.85(dd,1H,J
1＝5.6Hz,J
2＝13.6Hz,CH
2),2.60(dd,1H,J
1＝6.0Hz,J
2＝14.0Hz,CH
2),1.33(s,9H,3CH
3).
Embodiment 5:(R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol
Step (4-a): (R)-biphenylalanine
25% aqueous sulfuric acid 180mL of (R)-N-Benzoylbiphenyl alanine methyl ester (0.1mol, 36.0g) and new preparation is added, reflux in the there-necked flask of 500mL.TLC tracks to raw material point and reacts completely, and close heating, ice bath is cooled to 0 ~ 5 DEG C, slowly adds sodium hydroxide solution adjust ph to 5 ~ 6 of 10%, has a large amount of white solid to separate out.Suction filtration, vacuum-drying, obtains white solid product (R)-biphenylalanine 21.7g, and yield is 90.0%, chemical purity 99.1%, optical purity 99.1% (HPLC).
Step (5-a): (R)-phenylaniline propanol hydrochloride
Methyl alcohol 260mL, CuCl is added in the there-necked flask of 1L
2(0.09mol, 15.3g) and KBH
4(0.18mol, 9.7g), stirring at room temperature 1h, then the 1h that refluxes, stratification, get supernatant liquid, add the product (0.09mol, 21.7g) of step (4-a) gained, reflux, TLC tracks to raw material point and reacts completely, ice bath is cooled to 0 ~ 5 DEG C, adds the dilution of 200mL methyl tertiary butyl ether, adds suitable quantity of water termination reaction, add 20% potassium hydroxide aqueous solution 150mL again and stir 30min, filter, filter cake (3 × 20mL) methyl tertiary butyl ether washing, merges organic layer, anhydrous sodium sulfate drying, removes solvent under reduced pressure and obtains colorless oil.The ethanolic soln adding oily matter 5 times amount is clearly molten, and ice bath is cooled to 0 ~ 5 DEG C, drips concentrated hydrochloric acid, has a large amount of white solid to separate out.Suction filtration, vacuum-drying, obtain white solid product (R)-phenylaniline propanol hydrochloride 15.1g, yield is 63.6%, chemical purity 97.8%, optical purity 99.2% (HPLC).
Step (6): (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol
In 500mL there-necked flask, add the product (0.05mol, 13.1g) of step (5-a) gained, sodium hydroxide (0.15mol, 6g) and water 110mL, mechanical stirring, ice bath is cooled to 0 ~ 5 DEG C, adds tert-Butyl dicarbonate (0.065mol, 14.2g), remove ice bath, room temperature 25 ~ 30 DEG C reaction, has solid to separate out, and TLC tracks to raw material point and reacts completely.Suction filtration, vacuum-drying, obtain white solid product (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol 13.2g, yield is 80.6%, chemical purity 99.0%, optical purity 99.1% (HPLC).
Reaction formula 3:
Embodiment 6:(R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol
Step (4-b): (R)-2-kharophen biphenyl propyl alcohol
Tetrahydrofuran (THF) 370mL, MnCl is added in the there-necked flask of 1L
2(0.15mol, 24.3g) and NaBH
4(0.3mol; 11.4g), stirring at room temperature 1h, then the 1h that refluxes; stratification; get supernatant liquid, add (R)-N-acetyl biphenyl alanine ethyl ester (0.1mol, 31.1g); reflux; TLC tracks to raw material point and reacts completely, and removes tetrahydrofuran (THF) under reduced pressure, and add water making beating; a large amount of white solid is had to separate out; ice bath leaves standstill crystallization 3h, suction filtration, vacuum-drying; obtain white solid product (R)-2-kharophen biphenyl propyl alcohol 20.4g; yield is 75.8%, chemical purity 98.3%, optical purity 98.9% (HPLC).
1H-NMR(DMSO,400MHz)δ7.50-7.59(m,4H,Ar-H),7.41(d,2H,J＝8.0Hz,Ar-H),7.35(dd,1H,J
1＝7.6Hz,J
2＝8.0Hz,Ar-H),7.31(d,2H,J＝8.4Hz,Ar-H),5.93(d,1H,J＝5.6Hz,NH),4.70(s,1H,OH),3.61-3.65(m,1H,CH),3.38(dd,1H,J
1＝6.8Hz,J
2＝14.0Hz,CH
2),3.29(dd,1H,J
1＝7.2Hz,J
2＝14.0Hz,CH
2),2.84(dd,1H,J
1＝7.6Hz,J
2＝14.0Hz,CH
2),2.63(dd,1H,J
1＝7.2Hz,J
2＝14.0Hz,CH
2),2.03(s,3H,CH
3).
Step (5-b): (R)-2-phenylaniline propanol hydrochloride
The product (0.07mol, 18.8g) of step (4-b) gained and 20% aqueous hydrochloric acid 110mL of new preparation is added, reflux in the there-necked flask of 500mL.TLC tracks to raw material point and reacts completely.Concentrating under reduced pressure, adds the making beating of 100mL ethyl acetate, has a large amount of white solid to separate out.Suction filtration, filter cake 20mL ethyl acetate washs three times, vacuum-drying, obtains white solid 17.2g, and yield is 93.2%, chemical purity 99.4%, optical purity 99.0% (HPLC).
Step (6): (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol
In 500mL there-necked flask, add the product (0.05mol, 13.1g) of step (5-b) gained, salt of wormwood (0.2mol, 27.6g) and methylene dichloride 70mL, mechanical stirring, ice bath is cooled to 0 ~ 5 DEG C, adds tert-Butyl dicarbonate (0.07mol, 15.3g), remove ice bath, room temperature 25 ~ 30 DEG C reaction, has solid to separate out, and TLC tracks to raw material point and reacts completely.Suction filtration, vacuum-drying, obtain white solid product (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol 12.7g, yield is 77.6%, chemical purity 97.3%, optical purity 98.2% (HPLC).
Embodiment 7:(R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol
Step (4-b): (R)-2-benzamido biphenyl propyl alcohol
Methyl alcohol 360mL, LiCl (0.1mol, 4.2g) and KBH is added in the there-necked flask of 1L
4(0.2mol, 10.8g), stirring at room temperature 1h; reflux 1h again; stratification, gets supernatant liquid, adds (R)-N-Benzoylbiphenyl alanine methyl ester (0.1mol; 35.9g); reflux, TLC tracks to raw material point and reacts completely, and removes methyl alcohol under reduced pressure; add water making beating; have a large amount of white solid to separate out, ice bath cools, and leaves standstill crystallization 3h; suction filtration; vacuum-drying, obtain white solid product (R)-2-benzamido biphenyl propyl alcohol 24.0g, yield is 72.5%; chemical purity 98.7%, optical purity 98.3% (HPLC).
1H-NMR(DMSO,400MHz)δ7.85(d,2H,J＝6.8Hz,Ar-H),7.53-7.62(m,7H,Ar-H),7.44(d,2H,J＝8.4Hz,Ar-H),7.37(dd,1H,J
1＝7.6Hz,J
2＝8.0Hz,Ar-H),7.34(d,2H,J＝8.0Hz,Ar-H),6.71(d,1H,J＝6.0Hz,NH),4.75(s,1H,OH),3.63-3.67(m,1H,CH),3.36(dd,1H,J
1＝7.2Hz,J
2＝13.6Hz,CH
2),3.29(dd,1H,J
1＝7.2Hz,J
2＝14.0Hz,CH
2),2.89(dd,1H,J
1＝6.8Hz,J
2＝14.0Hz,CH
2),2.61(dd,1H,J
1＝7.2Hz,J
2＝14.0Hz,CH
2).
Step (5-b): (R)-2-phenylaniline propanol sulfate
The product (0.07mol, 23.2g) of step (4-b) gained and 30% aqueous sulfuric acid 130mL of new preparation is added, reflux in the there-necked flask of 500mL.TLC tracks to raw material point and reacts completely.Concentrating under reduced pressure, adds the making beating of 100mL ethyl acetate, has a large amount of white solid to separate out.Suction filtration, filter cake 20mL ethyl acetate washs three times, vacuum-drying, obtains white solid 21.1g, and yield is 92.6%, chemical purity 99.3%, optical purity 98.7% (HPLC).
Step (6): (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol
In 500mL there-necked flask, add the product (0.05mol, 16.4g) of step (5-b) gained, triethylamine (0.2mol, 20.2g) and tetrahydrofuran (THF) 100mL, mechanical stirring, ice bath is cooled to 0 ~ 5 DEG C, adds tert-Butyl dicarbonate (0.07mol, 15.3g), remove ice bath, room temperature 25 ~ 30 DEG C reaction, has solid to separate out, and TLC tracks to raw material point and reacts completely.Suction filtration, vacuum-drying, obtain white solid product (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol 11.2g, yield is 68.4%, chemical purity 96.5%, optical purity 97.3% (HPLC).
Reaction formula 4:
Embodiment 8:(R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol
Step (4-c): (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol
Tetrahydrofuran (THF) 680mL, CaCl is added in the there-necked flask of 1L
2(0.25mol, 27.7g) and NaBH
4(0.5mol, 27.0g), stirring at room temperature 1h, reflux 1h again, stratification, get supernatant liquid, add (R)-N-tertbutyloxycarbonyl biphenylalanine (0.25mol, 85.4g), reflux, TLC tracks to raw material point and reacts completely, remove tetrahydrofuran (THF) under reduced pressure, add water making beating, a large amount of white solid is had to separate out, ice bath leaves standstill crystallization 3h, suction filtration, vacuum-drying, obtain white solid product (R)-2-(N-t-butoxycarbonyl amino) biphenyl propyl alcohol 58.3g, yield is 71.3%, chemical purity 98.9%, optical purity 98.6% (HPLC).
It is pointed out that above-described embodiment is only and technical conceive of the present invention and feature are described, can not limit the scope of the invention with this.Those skilled in the art can make various distortion or amendment within the scope of the claims, and this does not affect flesh and blood of the present invention, all should be encompassed within protection scope of the present invention.
Claims (14)
1. a preparation method for (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in formula (I), it is characterized in that, described preparation method carries out as follows:
(1) Erlenmeyer-Plochl cyclization: under nitrogen protection,, under the existence of aceticanhydride and alkali, there is the oxazolone compound shown in Erlenmeyer-Plochl ring-closure reaction synthesis type (IV) in the N-acylglycine shown in the biphenylcarboxaldehyde shown in formula (II) and formula (III);
Wherein, R
1for methyl, phenyl or tert.-butoxy;
(2) hydrolysis or alcoholysis: the oxazolone compound shown in formula (IV) of step (1) gained, obtains the N-acyl group biphenyl propylene propylhomoserin shown in formula (V) or ester via hydrolysis or alcoholysis;
Wherein, R
1for methyl, phenyl, tert.-butoxy; R
2for hydrogen, methyl or ethyl;
(3) asymmetric hydrogenation: the N-acyl group biphenyl propylene propylhomoserin shown in formula (V) of step (2) gained or ester are under rhodium metal-biphosphine ligand catalyst, there is asymmetric hydrogenation in organic solvent, obtain (the R)-N-acyl diphenylalanine shown in formula (VI) or ester;
Wherein, R
1for methyl, phenyl or tert.-butoxy; R
2for hydrogen, methyl or ethyl;
(4-a) be hydrolyzed: (R)-N-acyl diphenylalanine shown in formula (VI) of step (3) gained or ester back hydrolysis under strong acid aqueous solution exists, synthesis (R)-biphenylalanine (formula VII);
Described strong acid aqueous solution is the aqueous hydrochloric acid of 5wt% ~ 30wt% or the aqueous sulfuric acid of 10wt% ~ 40wt%; The volumetric usage of described strong acid aqueous solution counts 4 ~ 6mL/g with the quality of substrate formula (VI);
(5-a) reduce: (the R)-biphenylalanine shown in formula (VII) of step (4-a) gained carries out (the 2R)-phenylaniline propyl alcohol shown in carboxyl reduction Reactive Synthesis formula (VIII) under sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system effect;
Described metal-salt system is alkaline earth metal chloride, lanthanide series metal muriate or transition metal chloride; The organic solvent that described carboxyl reduction reacts used is tetrahydrofuran (THF) or methyl alcohol; Described carboxyl reduction reaction is carried out under reflux conditions; In described sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system, sodium borohydride or POTASSIUM BOROHYDRIDE and metal-salt feeds intake amount of substance than being 1:0.1 ~ 1; Described carboxyl reduction reaction substrate formula (VII) is 1:1 ~ 5 with the amount of substance ratio that feeds intake of sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system; The volumetric usage of described organic solvent counts 8 ~ 12mL/g with the quality of substrate formula (VII);
(6) amido protecting: (the 2R)-phenylaniline propyl alcohol shown in formula (VIII) of step (5-a) gained in the basic conditions, react with tert-Butyl dicarbonate in organic solvent, (R)-3-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in synthesis final product formula (I);
Described alkaline condition alkali used is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, triethylamine or DMAP; Described organic solvent is water, methylene dichloride or tetrahydrofuran (THF); The temperature of reaction of described step (6) is 0 ~ 30 DEG C; (2R)-phenylaniline propyl alcohol shown in described formula (VIII) is 1:1 ~ 5:1 ~ 2 as reaction substrate and the ratio of the amount of substance that feeds intake of alkali, tert-Butyl dicarbonate; The volumetric usage of described organic solvent counts 5 ~ 10mL/g with the quality of substrate formula (VIII);
2. a preparation method for (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in formula (I),
It is characterized in that, described preparation method comprises step described in claim 1 (1), (2), (3),
When (R)-N-acyl diphenylalanine shown in formula (VI) of step described in preparation method (3) gained or ester are for (the R)-N-Benzoylbiphenyl L-Ala shown in (the R)-N-acetyl biphenyl L-Ala shown in formula (VIa) or ester or formula (VIb) or ester, described preparation method comprises step (4-b), (5-b), (6):
Wherein, R
2for hydrogen, methyl or ethyl;
(4-b) reduce: (the R)-N-acetyl biphenyl L-Ala shown in formula (VIa) of step (3) gained or ester or (the R)-N-Benzoylbiphenyl L-Ala shown in formula (VIb) or ester are under sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system effect, and (2R) shown in carboxyl reduction Reactive Synthesis formula (IXa)-(N-ethanoyl) phenylaniline propyl alcohol or (2R) shown in formula (IXb)-(N-benzoyl) phenylaniline propyl alcohol are carried out in backflow in organic solvent;
Described metal-salt system is alkaline earth metal chloride, lanthanide series metal muriate or transition metal chloride; The organic solvent that described carboxyl reduction reacts used is tetrahydrofuran (THF) or methyl alcohol; In described sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system, sodium borohydride or POTASSIUM BOROHYDRIDE and metal-salt feeds intake amount of substance than being 1:0.1 ~ 1; Described reduction reaction substrate formula (VIa) or formula (VIb) are 1:1 ~ 5 with the amount of substance ratio that feeds intake of sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system; The volumetric usage of described organic solvent counts 8 ~ 12mL/g with the quality of substrate formula (VII);
(5-b) be hydrolyzed: (2R) shown in formula (IXa)-(N-ethanoyl) the phenylaniline propyl alcohol of step (4-b) gained or (2R) shown in formula (IXb)-(N-benzoyl) phenylaniline propyl alcohol back hydrolysis under strong acid aqueous solution exists, (the 2R)-phenylaniline propyl alcohol shown in synthesis type (VIII);
Described strong acid aqueous solution is the aqueous hydrochloric acid of 5wt% ~ 30wt%, the aqueous sulfuric acid of 10wt% ~ 40wt%; The volumetric usage of described strong acid aqueous solution counts 4 ~ 6mL/g with the quality of substrate formula (VI);
(6) amido protecting: (the 2R)-phenylaniline propyl alcohol shown in formula (VIII) of step (5-a) gained in the basic conditions, react with tert-Butyl dicarbonate in organic solvent, (R)-3-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in synthesis final product formula (I);
Described alkaline condition alkali used is sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, triethylamine or DMAP; Described organic solvent is water, methylene dichloride or tetrahydrofuran (THF); The temperature of reaction of described step (6) is 0 ~ 30 DEG C; (2R)-phenylaniline propyl alcohol shown in described formula (VIII) is 1:1 ~ 5:1 ~ 2 as reaction substrate and the ratio of the amount of substance that feeds intake of alkali, tert-Butyl dicarbonate; The volumetric usage of described organic solvent counts 5 ~ 10mL/g with the quality of substrate formula (VIII);
3. a preparation method for (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in formula (I),
It is characterized in that, described preparation method comprises step described in claim 1 (1), (2), (3),
When (R)-N-acyl diphenylalanine shown in preparation method's formula (VI) or ester are for (the R)-N-tertbutyloxycarbonyl biphenylalanine shown in formula (VIc) or ester, described preparation method comprises step (4-c):
Wherein, R
2for hydrogen, methyl or ethyl;
(4-c) reduce: (the R)-N-tertbutyloxycarbonyl biphenylalanine shown in formula (VIc) of step (3) gained or ester are under sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system effect, and (R)-3-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in carboxyl reduction Reactive Synthesis synthesis final product formula (I) is carried out in backflow in organic solvent;
Described metal-salt system is alkaline earth metal chloride, lanthanide series metal muriate or transition metal chloride; Described reduction reaction organic solvent used is tetrahydrofuran (THF) or methyl alcohol; In described sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system, sodium borohydride or POTASSIUM BOROHYDRIDE and metal-salt feeds intake amount of substance than being 1:0.1-1; Described reduction reaction substrate formula (VIc) is 1:1 ~ 5 with the amount of substance ratio that feeds intake of sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system; The volumetric usage of described organic solvent counts 8 ~ 12mL/g with the quality of substrate formula (VII);
4. the preparation method of (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol according to described formula (I) arbitrary in claims 1 to 3, is characterized in that:
In described step (1), described alkali is sodium-acetate or Potassium ethanoate; The temperature of reaction of described Erlenmeyer-Plochl ring-closure reaction is 85 ~ 100 DEG C; Described biphenylcarboxaldehyde is 1:0.7 ~ 1.5:1 ~ 5:0.8 ~ 1.5 with the ratio of the amount of substance that feeds intake of N-acylglycine, aceticanhydride, alkali;
In described step (2), described hydrolysis agents useful for same is 0.1wt% ~ 10wt% aqueous sodium hydroxide solution or 0.1wt% ~ 10wt% potassium hydroxide aqueous solution; Described alcoholysis agents useful for same is 0.1wt% ~ 10wt% methanol solution of sodium methylate or 0.1wt% ~ 10wt% alcohol sodium alcohol solution; The temperature of reaction of described hydrolysis or alcoholysis is 40 ~ 100 DEG C; The volumetric usage of described hydrolysis agents useful for same or described alcoholysis agents useful for same counts 3 ~ 5mL/g with the quality of oxazolone compound substrate formula (IV) Suo Shi;
In described step (3), the temperature of reaction of described asymmetric hydrogenation is 30 ~ 100 DEG C, and in reaction system, hydrogen pressure is 0.5 ~ 3.0MPa, described asymmetric hydrogenation reaction solvent used is methyl alcohol, ethanol, Virahol, methylene dichloride or tetrahydrofuran (THF), the volumetric usage of described reaction solvent counts 4 ~ 6mL/g with the quality of substrate formula (V), described rhodium metal-biphosphine ligand catalyzer is (R)-[RhcodTCFP] BF4, [Rhcod (R)-DuanPhos] BF4, [Rhcod (R)-TangPhos] BF4, [Rhcod (R)-DuPhos] BF4, [Rhcod (R)-PhanePhos] BF4, [(R)-BinapRuClbenzene] Cl, [(R)-PPhosRuCl (p-cymene)] Cl, [(R)-xyl-PPhosRuCl (p-cymene)] Cl, shown in described rhodium metal-biphosphine ligand catalyzer and substrate formula (V), the ratio of the amount of substance that feeds intake of N-acyl group biphenyl propylene propylhomoserin or ester cpds is 1:10,000 ~ 120,000.
5., according to described preparation method arbitrary in claims 1 to 3, it is characterized in that, in described step (1), described biphenylcarboxaldehyde is 1:0.9 ~ 1.2:2 ~ 4:1 ~ 1.2 with the ratio of the amount of substance that feeds intake of N-acylglycine, aceticanhydride, alkali.
6. the preparation method of (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol according to described formula (I) arbitrary in claims 1 to 3, it is characterized in that, in described step (2), described hydrolysing agent is 0.5wt% ~ 5wt% aqueous sodium hydroxide solution or 0.5wt% ~ 5wt% potassium hydroxide aqueous solution; Described alcoholysis reagent is 0.5wt% ~ 5wt% methanol solution of sodium methylate or 0.5wt% ~ 5wt% alcohol sodium alcohol solution.
7. the preparation method of (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol according to described formula (I) arbitrary in claims 1 to 3, it is characterized in that, in described step (3), described rhodium metal-biphosphine ligand catalyzer is [Rhcod (R)-DuanPhos] BF4, [Rhcod (R)-TangPhos] BF4.
8. the preparation method of (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol according to described formula (I) arbitrary in claims 1 to 3; it is characterized in that; in described step (3); shown in described rhodium metal-biphosphine ligand catalyzer and substrate formula (V), the ratio of the amount of substance that feeds intake of N-acyl group biphenyl propylene propylhomoserin or ester cpds is 1:50; 000 ~ 100,000.
9. the preparation method of (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in formula according to claim 1 (I), it is characterized in that, in described step (4-a), described strong acid aqueous solution is the aqueous hydrochloric acid of 15wt% ~ 25wt%, the aqueous sulfuric acid of 25wt% ~ 35wt%.
10. the preparation method of (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in formula according to claim 2 (I), it is characterized in that, in described step (5-b), described strong acid aqueous solution is the aqueous hydrochloric acid of 15wt% ~ 25wt%, the aqueous sulfuric acid of 25wt% ~ 35wt%.
The preparation method of (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in 11. formulas (I) as claimed in claim 1, it is characterized in that, in step (5-a), described metal-salt is aluminum chloride, chlorinated ketone, calcium chloride, lithium chloride, Manganous chloride tetrahydrate, Lanthanum trichloride, zinc chloride; Described reaction substrate formula (VII) or formula (VIa) are 1:1.5 ~ 3 with the amount of substance ratio that feeds intake of sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system.
The preparation method of (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in 12. formulas (I) as claimed in claim 2, it is characterized in that, in step (4-b), described metal-salt is aluminum chloride, chlorinated ketone, calcium chloride, lithium chloride, Manganous chloride tetrahydrate, Lanthanum trichloride, zinc chloride; Described reaction substrate formula (VIb) is 1:1.5 ~ 3 with the amount of substance ratio that feeds intake of sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system.
The preparation method of (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in 13. formulas (I) as claimed in claim 3, it is characterized in that, in step (4-c), described metal-salt is aluminum chloride, chlorinated ketone, calcium chloride, lithium chloride, Manganous chloride tetrahydrate, Lanthanum trichloride, zinc chloride; Described reaction substrate formula (VIc) is 1:1.5 ~ 3 with the amount of substance ratio that feeds intake of sodium borohydride/metal-salt system or POTASSIUM BOROHYDRIDE/metal-salt system.
The preparation method of (R)-2-(N-t-butoxycarbonyl amino) the biphenyl propyl alcohol shown in 14. formulas (I) as claimed in claim 1 or 2, it is characterized in that, in described step (6), described (the 2R)-phenylaniline propyl alcohol shown in reaction substrate formula (VIII) is 1:2 ~ 4:1.2 ~ 1.4 with the ratio of the amount of substance that feeds intake of alkali, tert-Butyl dicarbonate.
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